regenerative medicine

UCLA-led team creates first comprehensive map of human blood stem cell development

/ Esteban Cortez / Leave a comment

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Human blood stem cells emerging from specialized endothelial cells in the wall of an embryonic aorta. UCLA scientists’ confirmation of this process clarifies a longstanding controversy about the stem cells’ cellular origin. Image Credit: Hanna Mikkola Lab/UCLA, Katja Schenke-Layland Lab/University of Tübingen, Nature

California researchers from UCLA and colleagues have created a first-of-its-kind roadmap that traces each step in the development of blood stem cells in the human embryo, providing scientists with a blueprint for producing fully functional blood stem cells in the lab. 

The research, published in the journal Nature, could help expand treatment options for blood cancers like leukemia and inherited blood disorders such as sickle cell disease, said UCLA’s Dr. Hanna Mikkola, who led the study. 

The California Institute for Regenerative Medicine (CIRM) has funded and supported Mikkola’s earlier blood stem cell research through various grants. 

Overcoming Limitations 

Blood stem cells, also called hematopoietic stem cells, can make unlimited copies of themselves and differentiate into every type of blood cell in the human body. For decades, doctors have used blood stem cells from the bone marrow of donors and the umbilical cords of newborns in life-saving transplant treatments for blood and immune diseases.  

However, these treatments are limited by a shortage of matched donors and hampered by the low number of stem cells in cord blood. 

Researchers have long sought to create blood stem cells in the lab from human pluripotent stem cells, which can potentially give rise to any cell type in the body. But success has been elusive, in part because scientists have lacked the instructions to make lab-grown cells become self-renewing blood stem cells rather than short-lived blood progenitor cells, which can only produce limited blood cell types. 

“Nobody has succeeded in making functional blood stem cells from human pluripotent stem cells because we didn’t know enough about the cell we were trying to generate,” said Mikkola. 

A New Roadmap

The new roadmap will help researchers understand the fundamental differences between the two cell types, which is critical for creating cells that are suitable for use in transplantation therapies, said UCLA scientist Vincenzo Calvanese, a co–first author of the research, along with UCLA’s Sandra Capellera-Garcia and Feiyang Ma. 

Researchers Vincenzo Calvanese and Hanna Mikkola. | Credit: Eddy Marcos Panos (left); Reed Hutchinson/UCLA

“We now have a manual of how hematopoietic stem cells are made in the embryo and how they acquire the unique properties that make them useful for patients,” said Calvanese, who is also a group leader at University College London.  

The research team created the resource using new technologies that enable scientists to identify the unique genetic networks and functions of thousands of individual cells and to reveal the location of these cells in the embryo. 

The data make it possible to follow blood stem cells as they emerge and migrate through various locations during their development, starting from the aorta and ultimately arriving in the bone marrow. Importantly, the map unveils specific milestones in their maturation process, including their arrival in the liver, where they acquire the special abilities of blood stem cells. 

The research group also pinpointed the exact precursor in the blood vessel wall that gives rise to blood stem cells. This discovery clarifies a longstanding controversy about the stem cells’ cellular origin and the environment that is needed to make a blood stem cell rather than a blood progenitor cell. 

Through these insights into the different phases of human blood stem cell development, scientists can see how close they are to making a transplantable blood stem cell in the lab. 

A Better Understanding of Blood Cancers

In addition, the map can help scientists understand how blood-forming cells that develop in the embryo contribute to human disease. For example, it provides the foundation for studying why some blood cancers that begin in utero are more aggressive than those that occur after birth. 

“Now that we’ve created an online resource that scientists around the world can use to guide their research, the real work is starting,” Mikkola said. “It’s a really exciting time to be in the field because we’re finally going to be seeing the fruits of our labor.” 

Read the full release here. 

Recovery from muscle loss injuries hindered by immune cell conflicts

/ Katie Sharify / Leave a comment

During a game in 2018, Alex Smith suffered a compound fracture that broke both the tibia and fibula in his right leg. The gruesome injury aside, the former 49ers quarterback soon developed life-threatening necrotizing fasciitis — a rare bacterial infection — that resulted in sepsis and required him to undergo 17 surgeries.

In a battle to save his life and avoid amputating his leg, doctors had to remove a great deal of his muscle tissue leading to volumetric muscle loss (VML). When Smith returned to the field after nearly two years of recovery, many called his comeback a “miracle”. 

Skeletal muscle is one of the most dynamic tissues of the human body. It defines how we move and can repair itself after injury using stem cells. However, when significant chunks of muscle are destroyed through severe injury (e.g. gunshot wound) or excessive surgery (like that of Smith’s), VML overwhelms the regenerative capacity of the muscle stem cells.

Despite the prevalence of these injuries, no standardized evaluation protocol exists for the characterization and quantification of VML and little is understood about why it consistently overwhelms the body’s natural regenerative processes. Current treatment options include functional free muscle transfer and the use of advanced bracing designs.

However, new research from the University of Michigan (U-M) may have just discovered why tissues often fail to regenerate from traumatic muscle loss injuries.

When researchers from U-M collaborated with partners at Georgia Tech, Emory University and the University of Oregon to study VML injuries in mice, they found that that sometimes post-injury immune cells become dysregulated and prevent stem cell repair. In VML injuries that don’t heal, neutrophils — a type of white blood cell — remain at the injured site longer than normal meaning that they’re not doing their job properly.

In addition, researchers found that intercellular communication between neutrophils and natural killers cells impacted muscle stem cell-mediated repair. When neutrophils communicated with natural killer cells, they were essentially prompted to self-destruct.

The findings suggest that by altering how the two cell types communicate, different healing outcomes may be possible and could offer new treatment strategies that eventually restore function and prevent limb loss. The team of researchers hope that better treatments could mean that recovery from VML injuries is no longer considered a “miracle”.

To read the source release, click here.

Educating and training the next generation of regenerative science workforce

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Bridges scholars presenting their research posters to CIRM team members and other scientists

Regenerative medicine is a diverse and rapidly evolving field, employing core expertise from biologists, engineers, and clinicians. As the field continues to advance, a well-trained regenerative science workforce is needed to apply the newest discoveries to clinical care. That’s why one of the goals outlined in our new 5-year Strategic Plan is to build a diverse and highly skilled workforce to support the growing regenerative medicine economy in California.  

Since its inception, the California Institute for Regenerative Medicine (CIRM) has been committed to educating the next generation of researchers, leaders, and innovators. Through its existing educational pillar programs such as SPARK and Bridges, the agency has been able to provide unique training and career development opportunities to a wide range of students from high school to college and beyond.

Through our new Strategic Plan, CIRM hopes to enhance training and education of the future California workforce by making it easier for students to start their career, accelerate career advancement, and provide greater access for diverse and underrepresented groups. Training and educating individuals who come from varied backgrounds brings new perspectives and different skillsets which enhance the development of the entire field, from basic and clinical research to manufacturing and commercialization.

The workforce training programs will be combined with CIRM’s other pillar programs to facilitate career entry at multiple levels. Through connecting the existing EDUC pillar programs with the planned California Manufacturing Network infrastructure program, CIRM hopes to address the critical need for a highly trained manufacturing workforce. By leveraging the Alpha Clinics and Community Care Centers, the agency will work to develop education curricula that address the currently unmet need for Clinical Research Coordinators. CIRM’s competency hubs and knowledge networks will also incorporate education and training programs to provide career pathways in emerging technologies, computational biology and data sciences.

You can read more about these goals in our 2022-27 Strategic Plan.

How these scholars are growing the regenerative medicine field in California

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CIRM Scholar Alessandra Rodriguez y Baena

Through our new Strategic Plan, the California Institute for Regenerative Medicine (CIRM) will build inclusive participation opportunities for all stakeholders, from the students to the workforce to the patients.  

That said, it’s important to recognize the important work CIRM has already done to train the next generation of scientists and grow the field of regenerative medicine. Alessandra’s story illustrates just one of the many ways we have done that in the past, and we intend to do even more in the future. 

Gaining Exposure to Innovative Research

CIRM Scholar Alessandra Rodriguez y Baena was a Master’s student at Cal Poly, San Luis Obispo. With the support of CIRM’s Bridges Program, she became a CIRM intern in the Willert Lab at UC San Diego.  

As a student researcher, CIRM provided her with supportive mentors (both at Cal Poly and UCSD), hands-on training in the field of regenerative medicine, and exposure to innovative ideas and research. The program also provided Alessandra with a stipend to help cover expenses. This was particularly helpful for students from low-income backgrounds who otherwise might not be able to afford to go to college. 

“I always recommend my undergraduate students who are interested in research to apply to the Bridges programs because, to me, it was a defining experience that led me to pursue my passion for stem cell research as well as teaching,” Alessandra says. 

Alessandra is now a fourth-year PhD student in the Forsberg Lab in the department of Molecular, Cell & Developmental Biology at UC Santa Cruz where she is studying the epigenetic regulation of aging in bone marrow stem cells.  

In addition to Alessandra, CIRM has provided opportunities in science to nearly 3,000 students across California. These include high schoolers in our SPARK Program, as well as undergrads and graduate students in our Bridges Program and pre and post-doctoral students in our Research Training program. Many of these are from diverse backgrounds.  

A Game Changer

Sneha Santosh, another CIRM Scholar, first heard about CIRM’s Bridges to Stem Cell Therapy and Research internship when she was graduating from the UC Davis. She was pursuing a degree in microbial biotechnology and thinking about getting a master’s degree in biotechnology. She said the opportunity to be part of a program that is training the next generation of scientists was a game changer for her.  

Through the Bridges Program, she learned about stem cells’ power to treat a disease’s root cause rather than just the symptoms. She saw how these transformative therapies changed people’s lives. 

Today, she is a cell culture associate with Novo Nordisk, a leading global healthcare company in Fremont, California 

CIRM’s New Strategic Plan

Alessandra and Sneha’s stories capture CIRM’s commitment to building education and training programs, and providing opportunities to build a diverse, highly skilled regenerative medicine workforce. We’ll be covering this ambitious yet achievable goal in our upcoming blog posts.  

To learn more about CIRM’s work and plans build the regenerative medicine field, check out our new 5-year strategic plan on our website.  

How a funny-looking creature could unlock the secrets of limb regeneration

/ Kevin McCormack / 2 Comments

The axolotl, also known as the Mexican salamander

In the world of funny-looking creatures, the Axolotl would have to rank in the top ten alongside such notables as the naked mole rat and the blob fish (the official mascot for the Ugly Animal Preservation Society). But the Axolotl does have one attribute that makes it attractive to more than just another Axolotl. That’s because this Mexican salamander has the ability to regenerate entire limbs.

Now, even as you read this, many stem cell researchers are hard at work trying to figure out ways to regenerate damaged or diseased tissues and organs in humans. That’s why the Axolotl is so intriguing. If we can understand how they are able to repair their own damaged limbs, maybe we can use that knowledge to help people repair or even replace a lost finger, hand or arm.

It’s a fascinating idea and one that is explored in this video from STAT, an online publication produced by the Boston Globe, that explores science and health.

It’s only four minutes long and is definitely worth watching. It shows that there is beauty in even the strangest creatures, if only you know what to look for.

How mice and zebrafish are unlocking clues to repairing damaged hearts

/ Kevin McCormack / Leave a comment

Bee-Gees

The Bee Gees, pioneers in trying to find ways to mend a broken heart. Photograph: Michael Ochs Archives

This may be the first time that the Australian pop group the Bee Gees have ever been featured in a blog about stem cell research, but in this case I think it’s appropriate. One of the Bee Gees biggest hits was “How can you mend a broken heart” and while it was a fine song, Barry and Robin Gibb (who wrote the song) never really came up with a viable answer.

Happily some researchers at the University of Southern California may succeed where Barry and Robin failed. In a study, published in the journal Nature Genetics, the USC team identify a gene that may help regenerate damaged heart tissue after a heart attack.

When babies are born they have a lot of a heart muscle cell called a mononuclear diploid cardiomyocyte or MNDCM for short. This cell type has powerful regenerative properties and so is able to rebuild heart muscle. However, as we get older we have less and less MNDCMs. By the time most of us are at an age where we are most likely to have a heart attack we are also most likely to have very few of these cells, and so have a limited ability to repair the damage.

Michaela Patterson, and her colleagues at USC, set out to find ways to change that. They found that in some adult mice less than 2 percent of their heart cells were MNDCMs, while other mice had a much higher percentage, around 10 percent. Not surprisingly the mice with the higher percentage of MNDCMs were better able to regenerate heart muscle after a heart attack or other injury.

So the USC team – with a little help from CIRM funding – dug a little deeper and did a genome-wide association study of these mice, that’s where they look at all the genetic variants in different individuals to see if they can spot common traits. They found one gene, Tnni3k, that seems to play a key role in generating MNDCMs.

Turning Tnni3K off in mice resulted in higher numbers of MNDCMs, increasing their ability to regenerate heart muscle. But when they activated Tnni3k in zebrafish it reduced the number of MNDCMs and impaired the fish’s ability to repair heart damage.

While it’s a long way from identifying something interesting in mice and zebrafish to seeing if it can be used to help people, Henry Sucov, the senior author on the study, says these findings represent an important first step in that direction:

“The activity of this gene, Tnni3k, can be modulated by small molecules, which could be developed into prescription drugs in the future. These small molecules could change the composition of the heart over time to contain more of these regenerative cells. This could improve the potential for regeneration in adult hearts, as a preventative strategy for those who may be at risk for heart failure.”

 

 

 

Fujifilm is Expanding Its Focus to Regenerative Medicine

/ Karen Ring / Leave a comment

Fujifilm began as a photography company, but today is a well-known multinational imaging and information technology corporation. More recently, it’s expanded its focus (pun intended) on developing innovative technologies in the healthcare and regenerative medicine space.

The news that Fujifilm was expanding into regenerative medicine was surprising to some given the company’s expertise in areas unrelated to stem cell research, but with the acquisition of Cellular Dynamics International, a company from Madison, Wisconsin that specializes in large-scale manufacturing of human cells, and the revamping of Fujifilm’s Japan Tissue Engineering subsidiary, which is developing regenerative treatments for damaged skin and cartilage, Fujifilm has solidified its position as a competitive company that’s accelerating the pace of regenerative medicine to develop treatments for patients with unmet medical needs.

Mr. Ban

Mr. Toshikazu Ban

So what progress has Fujifilm made in regenerative medicine and what advancements are they making towards the clinic? You’ll find the answers to these burning questions in my interview with Mr. Toshikazu Ban, Corporate Vice President, General Manager of Regenerative Medicine Business Division at Fujifilm Corporation. Enjoy!

Q: Why did Fujifilm decide to enter the regenerative medicine space?

TB: At first glance, Fujifilm may seem an unlikely candidate to become a leader in regenerative medicine, yet its engagement in the healthcare industry goes back many decades. Founded in 1934, Fujifilm started offering X-ray film just two years later. By 1983, Fujifilm became the first in the world to offer a digital X-ray diagnostic imaging system.

Today, Fujifilm has been able to expand the use of its core fundamental technologies in cosmetics and supplements and pharmaceuticals. Combined, these have allowed Fujifilm to transform into a major healthcare company committed to prevention, diagnosis and treatment.

Unfortunately, there are still many diseases for which there are no effective treatments, and millions wait in hope of their discovery. Regenerative medicine treatment has the potential to cure diseases that cannot be cured by drugs. Fujifilm feels a sense of responsibility to apply its technology in a way that helps make promising treatments a reality.

Q: What advantages do you think Fujifilm has over other healthcare companies in regenerative medicine?

TB: Fujifilm’s advanced engineering technology provides tremendous possibilities in the regenerative medicine space.

The chief component in photographic film is gelatin, which is derived from collagen. Fujifilm has developed a human-type recombinant peptide which can be scaffolds for growing cells and restoring tissue.  The human-type recombinant peptide is non-animal based, has high cellular adhesiveness, is flexible, safe, biocompatible, biodegradable and bioabsorbable. Cells survive better when they are combined with our recombinant peptide because it holds the cells better and allows space in between so that oxygen and other critical growth factors can reach the cells.

Fujifilm also has two subsidiaries that provide synergies and efficiencies to be more competitive in the regenerative medicine field, Cellular Dynamics International, Inc., (FCDI), and Japan Tissue Engineering Co., Ltd. (J-TEC).

In 2015, FCDI announced the launch of a stem cell bank with funding from CIRM to create induced pluripotent stem (iPS) cell lines for each of 3,000 healthy and diseased volunteer donors across 11 common diseases and disorders to be made available through the CIRM human pluripotent stem cell (hPSC) Repository.

The lines available from the CIRM stem cell bank directly complement FCDI’s ability to provide differentiated cells corresponding to each of the iPSC lines, which will allow researchers to model the diseases represented, better understand disease progression, perform more targeted drug discovery, and ultimately lead to better treatments.

A lot of pharmaceutical companies use these cells to test for the screening and toxicity of new drug candidates. If iPS cells can improve the productivity including efficacy and safety, the technology can greatly reduce time and cost as well as the drop-out rate in clinical development.

In 2014, J-TEC became a consolidated Fujifilm Group subsidiary. J-TEC launched the first two regenerative medicine products to receive approval from the Japanese government (one product is used to treat severe burns, while the other is used to replace damaged cartilage in knees).

J-TEC Lab (Image courtesy of Fujifilm)

J-TEC Lab (Image courtesy of Fujifilm)

Q: Can you describe some of the stem cell therapies you’re developing for the clinic for major diseases?

TB: FCDI plans to start iPS cell therapy clinical studies in the U.S. for age related macular degeneration in the year 2017, and clinical studies for retinitis pigmentosa, Parkinson’s and heart failure around 2019.

In March 2015, Fujifilm announced it had developed diabetes therapies in animal tests. CellSaic is a three-dimensional mosaic structure that combines cells with a recombinant peptide (RCP) scaffold made from micro-sized petaloid pieces of the protein. In a study involving type 1 diabetic mice, we created a CellSaic of human mesenchymal stem cells and cells from pancreatic islets and transplanted them in the mice. The purpose of the study was to verify whether using the recombinant peptide as a scaffold would increase the survival rate of the transplanted cells compared with just transplanting the cells alone. We also wanted to demonstrate a reduction in blood glucose levels of the diabetic mice since the recombinant peptide was able to sustain the viability of the pancreatic islet cells.

The study showed that seven days after the transplantation, CellSaic had a significantly more prominent introduction of blood vessels, which provide passageways for nutrients, oxygen and waste product to get to, and away from, the cells.  In addition, 28 days after transplantation, the test group of diabetic mice with the recombinant peptide-based CellSaic scaffold saw blood glucose levels lowered to the level equivalent to that of the healthy mice. In contrast, the diabetic mice who received pancreatic islets alone showed no change in blood glucose levels. 

Q: When you move into clinical trials, do you anticipate US trial sites in parallel with those in Japan?

TB: FCDI plans to start clinical trials of iPS cell treatments in the US. J-TEC conducts clinical trials for autologous cultured corneal epithelium and plans to start clinical trials for allogeneic cultured dermis in Japan. Currently we plan to conduct these clinical trials where these companies are located. We may expand the clinical trials of the products to other countries in the future.

Q: Can you speak to Japan’s regulatory system for stem cell therapies and how this could give Fujifilm a leg up on developing stem cell treatments more rapidly?

TB: The go-to market conditions for regenerative medicine in Japan have become more favorable since the November 2014 implementation of the Pharmaceutical and Medical Device Law, which has significantly cut the time it takes to gain marketing approval in Japan and created more interest in this sector.

Within regenerative medicine, academic institutions have shown remarkable progress. The mission of the industry is to apply findings from academia to patients and deliver high-quality treatments at a reasonable cost.

Note: Technologies that pertain to Japan Tissue Engineering Co., Ltd. (J-TEC) are not approved for use in the US.

You can learn more about Fujifilm’s latest efforts to “make regenerative medicine a reality” by visiting its Innovation website.

Getting On Tract: Stem Cells Regenerate Injured Spinal Cord in Rats

/ Karen Ring / Leave a comment

a6353-spinalcordThe spinal cord acts as a highway that transports electrical signals from your brain to the rest of your body through long bundles of nerve fibers. It allows your brain to communicate with the rest of your body to coordinate movement and reflexes and to receive sensory information. When the spinal cord is damaged, the nerve fibers, which are also called axons, are crushed or severed. This important communication highway is disrupted, leaving patients partially or fully paralyzed and severely reducing their quality of life.

Stem cell treatments for spinal cord injury

Scientists are pursuing multiple strategies using stem cells to treat spinal cord injury. Some involve transplanting cells derived from pluripotent stem cells or from stem cells isolated from human tissue. Both types of stem cells can be manipulated to develop into new nerve cells that can replace those that have died or into new support cells that coax damaged nerve cells to regrow their axons. Others are transplanting stem cells at the site of injury to prevent further damage by reducing tissue scarring and inflammation or by releasing protective factors that keep the remaining nerve and support cells healthy.

Repairing a damaged spinal cord is no easy task. Stem cell treatments tested in animal models have only shown partial recovery of motor function, and clinical trials using stem cells to treat spinal cord injury in humans are still in their early stages (read more about clinical trials here).

However, a group from UC San Diego is on “tract” (pardon the pun) to develop a novel treatment that might one day regenerate damaged spinal cords in humans. They published their exciting study in Nature Medicine yesterday suggesting that stem cells can regenerate injured spinal cords – at least in rats.

Getting on tract to regenerate injured spinal cords

The team grafted neural stem cells derived from rat embryonic stem cells into the injured spinal cords of rats. These stem cells developed into functional nerve cells that replaced damaged axons in the corticospinal tract, which is bundle of nerve fibers in the spinal cord that originates in the cerebral cortex of the brain and controls basic motor function. Injured rats that received stem cell grafts showed improvements in their ability to move their forelimbs.

Transplanted neural stem cells (green) shown in the corticospinal tract (red) develop into new neurons (purple). (Nature Medicine)

Transplanted neural stem cells (green) shown in the corticospinal tract (red) develop into new neurons (purple). (Nature Medicine)

The authors also grafted neural stem cells derived from human embryonic stem cells into injured spinal cords of rats and observed evidence of spinal cord regeneration and newly generated corticospinal axons.

The study’s senior author, Dr. Mark Tuszynski, explained in a UC San Diego Health news release that their study is the first to regenerate the corticospinal tract in rats using neural stem cells. While this work is in its early stages, Dr. Tuszynski believes that his group’s work has the potential to be translated into a treatment for human spinal cord injury:

Mark Tuszynski, UCSD

Mark Tuszynski, UCSD

“We humans use corticospinal axons for voluntary movement. In the absence of regeneration of this system in previous studies, I was doubtful that most therapies taken to humans would improve function. Now that we can regenerate the most important motor system for humans, I think that the potential for translation is more promising.”

 

However, when translating any stem cell therapy from animals into humans, safety and efficacy are a top priority. Dr. Tuszynski acknowledged these hurdles and shared his plan for future studies:

“There is more work to do prior to moving to humans. We must establish long-term safety and long-term functional benefit in animals. We must devise methods for transferring this technology to humans in larger animal models. And we must identify the best type of human neural stem cell to bring to the clinic.”

As a side note, CIRM has funded earlier translational research by Dr. Tuszynski. You can read more about his CIRM-funded research project to develop novel stem cell treatments for spinal cord injury here.

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How you derive embryonic stem cells matters

/ Karen Ring / 1 Comment

A scientist named James Thompson was the first to successfully culture human embryonic stem cells in 1998. He didn’t know it then, but his technique isolated a specific type of embryonic stem cell (ESC) that had a “primed pluripotent state”.

There are actually two phases of pluripotency: naïve and primed. Naïve ESCs occur a step earlier in embryonic development (during the beginning of the blastocyst stage), and the naïve state can be thought of as the ground state of pluripotency. Primed ESCs on the other hand are more mature and while they can still become every cell type in the body, they are somewhat less flexible compared to naïve ESCs. If you want to learn more about naïve and primed ESCs, you can refer to this scientific review.

Scientists have developed methods to derive both naïve and primed human ESCs in culture and are attempting to use these cells for biomedical applications. However, a recent CIRM-funded study published in Cell Stem Cell, calls into question the quality of ESCs produced using these culturing methods and could change how lab-derived stem cells are used for stem cell transplant therapies and regenerative medicine.

Primed human embryonic stem cells (purple) identified by a green stem cell surface marker. (Image courtesy of UCLA)

Primed human embryonic stem cells (purple) identified by a green stem cell surface marker. (Image courtesy of UCLA)

Culturing methods erase stem cell memory

UCLA scientists discovered that some of the culturing methods used to propagate naïve ESCs actually erase important biochemical signatures that are essential for maintaining ESCs in a naïve state and for passing down genetic information from the embryo to the developing fetus.

When they studied naïve ESCs in culture, they focused on a naturally occurring process called DNA methylation. It controls which genes are active and which are silenced by adding chemical tags to certain stretches of DNA called promoters, which are responsible for turning genes on or off. This process is critical for normal development and keeping cells functional and healthy in adults.

UCLA scientists compared the DNA methylation state of the mature human blastocyst – the early-stage embryo and where naïve ESCs come from – to the methylation state of naïve ESCs generated in culture. They found that the methylation patterns in the blastocyst six days after fertilization were the same as the patterns found in the egg that it developed from. This discovery is contrary to previous beliefs that the DNA methylation patterns in eggs are lost a few hours after fertilization.

Amander Clark, the study’s lead author and UCLA professor explained in a UCLA news release:

Amander+Clark+headshot_68295d00-2717-4d5c-99f3-f791e6b6ebcf-prv

Amandar Clark, UCLA

“We know that the six days after fertilization is a very critical time in human development, with many changes happening within that period. It’s not clear yet why the blastocyst retains methylation during this time period or what purpose it serves, but this finding opens up new areas of investigation into how methylation patterns built in the egg affect embryo quality and the birth of healthy children.”

The group also discovered cultured naïve ESCs lack these important DNA methylation patterns seen in early-stage blastocysts. Current methods to derive naïve ESCs wipe their memory leaving them in an unstable state. This is an issue for researchers because some prefer the use of naïve ESCs over primed ESCs for their studies because naïve ESCs have more potential for experimentation.

“In the past three years, naïve stem cells have been touted as potentially superior to primed cells,” Clark said. “But our data show that the naïve method for creating stem cells results in cells that have problems, including the loss of methylation from important places in DNA. Therefore, until we have a way to create more stable naïve embryonic stem cells, the embryonic stem cells created for the purposes of regenerative medicine should be in a primed state in order to create the highest-quality cells for differentiation.”

How you derive embryonic stem cells matters

Now that this culturing problem has been identified, the UCLA group plans to develop new and improved methods for generating naïve ESCs in culture such that they retain their DNA methylation patterns and are more stable.

The hope from this research is that scientists will be able to produce stem cells that more closely resemble their counterparts in the developing human embryo and will be better suited for stem cell therapies and regenerative medicine applications.

Related Links:

What Went Down at ARM’s Regenerative Medicine State of the Industry

/ Karen Ring / Leave a comment

Every January, downtown San Francisco is taken over by a flock of investors, bankers, biotech companies, and scientists attending the annual JP Morgan Healthcare Conference. This meeting looks at the healthcare advancements over the past year and predicts the disease areas and technologies that will see the most progress and success in 2016.

According to some of the experts at the event, regenerative medicine and stem cell research are experiencing impressive, accelerated advancements, which has peaked the interest of investors, biotech, and pharmaceutical companies.

Because these are such fast paced fields, the Alliance for Regenerative Medicine (ARM) hosts the Annual Regenerative Medicine and Advanced Therapies State of the Industry Briefing during JP Morgan to discuss the recent progress and outlook for the industry in the coming year.

Screen Shot 2016-01-11 at 4.03.30 PM

What happened in 2015 and what’s next?

ARM’s  6th Annual Briefing was open to the public and drew over 300 people on Monday morning. The meeting opened with an industry update from Edward Lanphier, ARM Chairman and President/CEO of Sangamo BioSciences.  Then two panels featuring top leaders from biotech and pharmaceutical companies discussed the 2016 clinical data forecast and the promise of regenerative medicine and advanced therapies in oncology (cancer).

With an upbeat attitude, Lanphier gave an overview of clinical development progress in 2015, with 20 approved products worldwide and over 600 clinical trials both from academia and industry. More than 40% of these ongoing clinical trials are in cancer while approximately 12% are in heart disease/injury. These trials are not limited to Phase 1 either. In 2015, there were 376 in Phase 2 (compared to 200 in 2014) and 64 in Phase 3 (compared to 39 in 2014).

Edward Lanphier

Edward Lanphier

Two other areas Lanphier emphasized were CAR-T and other cell-based immunotherapies and gene therapy programs for rare diseases. He ended with 2015 statistics on clinical milestones in various disease and therapy programs, key company IPOs, the financial landscape, and predictions of major anticipated data from clinical trials in 2016.

It was a lot to take in, but this was definitely a good thing and a sign that the areas of regenerative medicine and advanced therapies are thriving. If you want more details, you can check out ARM’s State of the Industry presentation.

Major Theme: Data is King

The major theme that cropped up during the industry update and panel discussions was the importance of producing meaningful clinical data to get positive outcomes in regenerative medicine.

This was succinctly put by panelist Sven Kili, head of Gene Therapy Development at GlaxoSmithKline:

“I would say “Data is King”. A great idea is fantastic, passion is wonderful, and most companies will buy into a strong management team, but that only gets you so far. After that you need to have data, and you need to have a good plan for going forward.”

Kill added that there’s the need to work with the FDA to change the regulatory process, saying the FDA is, understandably, cautious about working with therapies that can alter a person’s genome permanently. However, he said there needs to be serious discussions with the FDA about how to speed up the process, to make it easier for the most promising projects to get approval.

Edward Lanphier also talked about the industry’s new focus on clinical data and the questions that arise when trying to advance regenerative medicine research into approved treatments and cures for patients:

“How do we communicate the value of curing blindness? How do we think about pricing that? What do we think about [drug] reimbursement?  For rare diseases, we aren’t trying to talk about acute treatments – we are talking about one-time, curative outcomes. And the value and benefit to patients in this is enormous. This is what we are trying to do, and on the cusp of, in terms of generating both approvable data and also the proof of concept data that then allows us to drive that next value inflection point in terms of financings.”

The Future Looks Good

After listening to the briefing, the future of regenerative medicine and advanced therapies certainly looks bright. As Jason Kolbert, head of Healthcare Research at the Maxim Group, said:

“This industry is now rapidly maturing and regenerative medicine and gene therapy have great things in store for the next decade.”

Usman Azam, Global Head of Cell and Gene Therapies at Novartis, had a similar outlook:

“We now are going from proof of concept to commercial availability of a disruptive innovation within seven years. If somebody had said that to me four years ago, I would have said, not possible. But that gives you a sense of how quickly this field is moving.”

Experts Panel

ARM Panel: 2016 Sector Forecast: Upcoming Clinical Data Events